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Adoptively transferred donor IL-17-producing CD4⁺ T cells augment, but IL-17 alleviates, acute graft-versus-host disease.

ABSTRACT: The role of IL-17 and IL-17-producing CD4⁺ T cells in acute graft-versus-host disease (GVHD) has been controversial in recent mouse and human studies. We carried out studies in a murine acute GVHD model of fully major histocompatibility complex-mismatched myeloablative bone marrow transplantation. We showed that donor wild-type CD4⁺ T cells exacerbated acute GVHD compared with IL-17^-/- CD4⁺ T cells, while IL-17 reduced the severity of acute GVHD. The augmentation of acute GVHD by transferred donor IL-17-producing CD4⁺ T cells was associated with increased Th1 responses, while IL-17 decreased the percentages of Th1 cells in the GVHD target organs. Furthermore, IL-17 reduced the infiltration of macrophages into the GVHD tissues. In vitro study showed that IL-17 could downregulate Th1 responses, possibly through inhibiting IL-12 production by donor macrophages. Depletion of macrophages in vivo diminished the protective effect of IL-17. Our results demonstrated the differential roles of adoptively transferred donor IL-17-producing CD4⁺ T cells and IL-17 in the same acute GVHD model.

SUBMITTER: Cai Y

PROVIDER: S-EPMC5843609 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Adoptively transferred donor IL-17-producing CD4+ T cells augment, but IL-17 alleviates, acute graft-versus-host disease.

Cai Yifeng Y Ma Shoubao S Liu Yuejun Y Gong Huanle H Cheng Qiao Q Hu Bo B Wu Yan Y Yu Xiao X Dong Chen C Sun Kai K Wu Depei D Liu Haiyan H

Cellular & molecular immunology 20161017 3

The role of IL-17 and IL-17-producing CD4+ T cells in acute graft-versus-host disease (GVHD) has been controversial in recent mouse and human studies. We carried out studies in a murine acute GVHD model of fully major histocompatibility complex-mismatched myeloablative bone marrow transplantation. We showed that donor wild-type CD4+ T cells exacerbated acute GVHD compared with IL-17-/- CD4+ T cells, while IL-17 reduced the severity of acute GVHD. The a ...[more]

PMID: 27748733

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Project description:BackgroundAdoptive T cell transfer (ACT) therapy improves outcomes in patients with advanced malignancies, yet many individuals relapse due to the infusion of T cells with poor function or persistence. Toll-like receptor (TLR) agonists can invigorate antitumor T cell responses when administered directly to patients, but these responses often coincide with toxicities. We posited that TLR agonists could be repurposed ex vivo to condition T cells with remarkable potency in vivo, circumventing TLR-related toxicity.MethodsIn this study we investigated how tumor-specific murine CD8+ T cells and human tumor infiltrating lymphocytes (TILs) are impacted when expanded ex vivo with the TLR9 agonist CpG.ResultsHerein we reveal a new way to reverse the tolerant state of adoptively transferred CD8+ T cells against tumors using TLR-activated B cells. We repurposed the TLR9 agonist, CpG, commonly used in the clinic, to bolster T cell-B cell interactions during expansion for ACT. T cells expanded ex vivo from a CpG-treated culture demonstrated potent antitumor efficacy and prolonged persistence in vivo. This antitumor efficacy was accomplished without in vivo administration of TLR agonists or other adjuvants of high-dose interleukin (IL)-2 or vaccination, which are classically required for effective ACT therapy. CpG-conditioned CD8+ T cells acquired a unique proteomic signature hallmarked by an IL-2RαhighICOShighCD39low phenotype and an altered metabolic profile, all reliant on B cells transiently present in the culture. Likewise, human TILs benefitted from expansion with CpG ex vivo, as they also possessed the IL-2RαhighICOShighCD39low phenotype. CpG fostered the expansion of potent CD8+ T cells with the signature phenotype and antitumor ability via empowering a direct B-T cell interaction. Isolated B cells also imparted T cells with the CpG-associated phenotype and improved tumor immunity without the aid of additional antigen-presenting cells or other immune cells in the culture.ConclusionsOur results demonstrate a novel way to use TLR agonists to improve immunotherapy and reveal a vital role for B cells in the generation of potent CD8+ T cell-based therapies. Our findings have immediate implications in the clinical treatment of advanced solid tumors.

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Adoptively transferred donor IL-17-producing CD4⁺ T cells augment, but IL-17 alleviates, acute graft-versus-host disease.

Publications

Adoptively transferred donor IL-17-producing CD4<sup>+</sup> T cells augment, but IL-17 alleviates, acute graft-versus-host disease.

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